Compounds containing the benzothiophene nucleus exhibit a broad range of pharmacological activities. Triaryl ethylene derivatives exhibiting estrogenic and/or estrogen antagonist properties have shown anti-fertility properties in rodents, as have several 4-aminobenzo[b]thiophenes, tetrahydrodibenzothiophene carboxylic acids, and 4-keto-4,5,6,7-tetrahydrobenzo[b]thiophenes. A number of phenyl- and thienyl-substituted benzo[b]thiophene acetic acids, 2-arylbenzo[b]thiophen-3(2H)-one 1,1-dioxides, benzo[b][2,3-d]pyrimidines, and benzo[b]thiophene 2- and 3-acetic acid derivatives exhibit anti inflammatory activity in rodents.
Useful anti-adrenergic and anti-anginal activities have been attributed to 3-(4-dialkylaminoalkoxy-3,5-disubstituted)benzoylbenzo[b]thiophenes and anti-hypertensive and/or diuretic properties to certain 2-imidazolinylaminobenzo[b]thiophenes, cyclopenta[b]-benzo[b]thiophen-3-ones and sulfonamide derivatives of 2,3-dihydrobenzo[b]-thiophene 1,1dioxides. Sulfur analogs of several thiosemicarbazone derivatives, including a series of benzo[b]-thiophene-2- and 3-carboxaldehyde thiosemicarbazones exhibit significant anti-fungal and anti-viral activities; benzo[b]thiophene analogs of 3-methoxymethyl-7-acylaminocephalosporins reportedly possess antibacterial actions.
Centrally active benzo[b]thiophene derivatives include isosteres of psilocin and 5-hydroxytryptamine (serotonin). Several 1H-[1]benzo[b]thieno[2,3-c]pyran derivatives exhibit antidepressant activity, as do amides of benzo[b]thiophene-2carboxylic acids such as 3-bromo-2-(N-morpholinoethyl)benzo[b]thiophene carboximide, which additionally possesses anticonvulsant properties. Central nervous system depressant activity has been claimed for a number of N-[(4-phenyl-1-piperazinyl)alkyl]benzo[b]thiophene-2-carboxyamide and 3-substituted-2,3-dihydro-1H-cyclopenta[b]benzo[b]thiophenes; amides of 2-(3-benzo[b]thienyl)ethylamine and a series of 4-benzo[b]thienyloxyalkyl amidoxines reportedly reduce aggressive behavior in rodents (T. Bosin and E. Campaigne, Adv in Drug Res (1977), 11:191-233).
The compounds of the present invention are 1,2,3,4-tetrahydrobenzo[b]thienopyridines, sulfur-containing analogs of tetrahydronorharman, a naturally-occurring plant and animal alkaloid. Little is known about the biological activities of these benzothiophene derivatives apart from the fact that they reportedly inhibit antisocial behavior, cause central nervous system depression, and reduce spontaneous motor activity in several mammalian species (U.S. Pat. No. 3,636,218; U.S. Pat. No. 3,518,278; Miller et al, The Pharmacologist (1971) 3:207).
Central monoamine neurotransmitter systems have long been implicated in the regulation of ingestive behavior. Virtually all anorectic agents in current clinical use act upon catecholamine and/or serotonergic mechanisms. Those acting principally upon catecholamine systems possess significant stimulant properties; those acting on serotonergic systems do not. Although stimulant agents reduce food consumption and can lead to significant short-term weight loss, their ethical forms are more frequently abused and produce a higher incidence of adverse side effects than their non-stimulant counterparts.
1,2,3,4-tetrahydrobenzo[b]thieno[2,3-c]pyridine and several substituted derivatives have been disclosed in U.S. Pat. Nos. 3,636,218 and 3,518,278 and claimed as CNS depressants and tranquilizing agents. However, there is no disclosure of anorectic activity.